1,2,3,4-tetrahydroisoquinoline derivatives and pharmaceutical composition thereof

Abstract

The invention relates to compounds of formula (I) ##STR1## wherein R 1 is an optional substituent any position of phenyl ring and is selected from halogen, --NO 2 , --NH 2 , --OH and --O--CR 1-6 alkyl; --CH 2 R 2 is a substituent at 1- or 3- position of 1,2,3,4-tetrahydroisoquinoline, wherein R 2 is an azole group such as imidazole or triazole; and R 3 is phenyl optionally substituted with one or more halogen, and pharmaceutical salts thereof. The compounds of formula (I) and salts thereof are useful as antifungal agents. The invention also relates to the antifungal pharmaceutical compositions containing the compounds of formula (I), the methods of treating fungal infections using the compounds of formula (I) and the process for preparing the compounds of formula (I).

We claim: 
     
       1. A compound of formula (I) ##STR7## wherein R 1  is an optional substitution at any position of the phenyl ring and is selected from halogen, --NO 2 , --NH 2 , --OH, --O--C 1-6  alkyl; --CH 2  R 2  is a substitution at the 1- or 3- position of 1,2,3,4-tetrahydroisoquinoline, wherein R 2  is an azole group selecting from the group consisting of pyrrole, pyrazole, carbazole, benzimidazole, imidazole and triazole; and   R 3  is phenyl optionally substituted with one or more halogen; and pharmaceutical salts thereof.     
     
     
       2. A compound of claim 1, wherein R 2  is a triazolyl, imidazolyl or benzimidazolyl group. 
     
     
       3. A compound of claim 1 which is selected from the group consisting of: 2-Phenylmethyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Chlorophenyl)methyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Fluorophenyl)methyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Dichlorophenyl)methyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Difluorophenyl)methyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-Phenylmethyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Chlorophenyl)methyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Fluorophenyl)methyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Dichlorophenyl)methyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Difluorophenyl)methyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-Phenylmethyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Chlorophenyl)methyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Fluorophenyl)methyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Dichlorophenyl)methyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Difluorophenyl)methyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   (S)-2-Phenylmethyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2-Chlorophenyl)methyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2-Fluorophenyl)methyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Dichlorophenyl)methyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Difluorophenyl)methyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   2-Phenylmethyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Chlorophenyl)methyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Fluorophenyl)methyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   2-(2,4-Dichlorophenyl)methyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   2-(2,4-Difluorophenyl)methyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   (S)-2-Phenylmethyl-3-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Chlorophenyl)methyl-3-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Fluorophenyl)methyl-3-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   (S)-2-(2,4-Dichlorophenyl)methyl-3-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Difluorophenyl)methyl-3-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-Phenylcarbonyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Chlorophenyl)carbonyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Fluorophenyl)carbonyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Dichlorophenyl)carbonyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Difluorophenyl)carbonyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-Phenylcarbonyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Chlorophenyl)carbonyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Fluorophenyl)carbonyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Dichlorophenyl)carbonyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Difluorophenyl)carbonyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-Phenylcarbonyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Chlorophenyl)carbonyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Fluorophenyl)carbonyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Dichlorophenyl)carbonyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Difluorophenyl)carbonyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-Phenylcarbonyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Chlorophenyl)carbonyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Fluorophenyl)carbonyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Dichlorophenyl)carbonyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Difluorophenyl)carbonyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   2-Phenylcarbonyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Chlorophenyl)carbonyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Fluorophenyl)carbonyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Dichlorophenyl)carbonyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   2-(2,4-Difluorophenyl)carbonyl-1-(1H-1,3-benzimidazole-1-l)methyl-1,2,3,4-tetrahydro-isoquinoline;   (S)-2-Phenylcarbonyl-3-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Chlorophenyl)carbonyl-3-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Fluorophenyl)carbonyl-3-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   (S)-2-(2,4-Dichlorophenyl)carbonyl-3-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline; and   (S)-2-(2,4-Difluorophenyl)carbonyl-3-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline.   
     
     
       4. A compound of claim 3 which is selected from the group consisting of: 2-Phenylmethyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Chlorophenyl)methyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Fluorophenyl)methyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Dichlorophenyl)methyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Difluorophenyl)methyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-Phenylmethyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Chlorophenyl)methyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Fluorophenyl)methyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Dichlorophenyl)methyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Difluorophenyl)methyl-3-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-Phenylmethyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Chlorophenyl)methyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Fluorophenyl)methyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Dichlorophenyl)methyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(2,4-Difluorophenyl)methyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   (S)-2-Phenylmethyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Chlorophenyl)methyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(4-Fluorophenyl)methyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Dichlorophenyl)methyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   (S)-2-(2,4-Difluorophenyl)methyl-3-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   2-Phenylmethyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Chlorophenyl)methyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline;   2-(4-Fluorophenyl)methyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   2-(2,4-Dichlorophenyl)methyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline;   2-(2,4-Difluorophenyl)methyl-1-(1H-1,3-benzimidazole-1-yl)methyl-1,2,3,4-tetrahydro-isoquinoline.   
     
     
       5. The compound of claim 3 which is 2-(4-Chlorophenyl) methyl-1-(1H-1,2,4-triazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline. 
     
     
       6. The compound of claim 3 which is 2-(4-Chlorophenyl) methyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline. 
     
     
       7. The compound of claim 3 which is 2-(2,4-Dichlorophenyl)methyl-1-(1H-1,3-imidazole-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline. 
     
     
       8. A pharmaceutical composition for inhibiting fungal growth which comprises an effective fungal inhibitory amount of the compound of claim 1 in a pharmaceutically acceptable carrier. 
     
     
       9. A pharmaceutical composition for inhibiting fungal growth which comprises an effective fungal inhibitory amount of the compound of claim 3 in a pharmaceutically acceptable carrier. 
     
     
       10. A method of inhibiting fungal growth which comprises administrating an effective fungal inhibitory amount of the compound of claim 1. 
     
     
       11. A method of inhibiting fungal growth which comprises administrating an effective fungal inhibitory amount of the compound of claim 3.